Aqueous compositions containing metronidazole

ABSTRACT

An aqueous solution of metronidazole in which the concentration of metronidazole is higher than 0.75%. The solution contains a combination of solubility-enhancing agents, one of which is a cyclodextrin such as beta-cyclodextrin and the second is niacin or niacinamide. Methods of manufacture and therapeutic use of the solution are disclosed.

This is a continuation application claiming priority from U.S. patentapplication Ser. No. 10/033,835 filed Dec. 24, 2001 now U.S. Pat. No.6,881,726.

FIELD OF THE INVENTION

The invention pertains to the field of topically applied medications fortreatment of skin and mucosal disorders. In particular, the inventionpertains to aqueous compositions containing metronidazole as the activeingredient.

BACKGROUND OF THE INVENTION

Metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, has longbeen known as an effective drug to treat a variety of disorders, and isespecially well known for the treatment of various protozoal diseases.As a topical therapy, metronidazole has also been shown to be useful intreating various skin disorders, including acne rosacea, bacterialulcers, and perioral dermatitis. See, Borgman, U.S. Pat. No. 4,837,378.Metronidazole has been found to have an anti-inflammatory activity whenused topically to treat dermatologic disorders. See, Czernielewski, etal., U.S. Pat. No. 5,849,776. Metronidazole may also be used as anintravaginal therapeutic agent for the treatment of bacterial vaginosis.See, Borgman, U.S. Pat. No. 5,536,743.

Compositions containing metronidazole for treatment of dermatologicdisorders are available in cream, lotion and gel forms. One commerciallyavailable metronidazole cream product, NORITATE™ (Dermik Laboratories,Inc., Collegeville, Pa. 19426 USA) contains 1% metronidazole in whichthe insoluble drug is suspended in the opaque cream. A commerciallyavailable metronidazole gel product, METROGEL® (Galderma Laboratories,Inc. Fort Worth, Tex., 76133 USA), contains 0.75% metronidazole which issolubilized to produce a clear gel.

For the treatment of many dermatologic and mucosal disorders, it isoften preferable to use a solubilized water-based formulation, such as agel, rather than a cream, lotion or an ointment. Creams, lotions(typically oil in water emulsions) and ointments (typically petroleumjelly based compositions) are often comedogenic, acnegenic, or notcosmetically appealing to patients. Solubilized topical products aregenerally more bioavailable than products in which the active ingredientis insoluble.

The oil-based cream and ointment metronidazole formulations have anadvantage over presently available gel-based formulations in thatoil-based formulations may contain a concentration of metronidazole of1%. Aqueous-based gel compositions are limited to a concentration ofmetronidazole of 0.75% because of the poor solubility of metronidazolein water.

Cyclodextrins have been shown to enhance the solubility of various drugsin aqueous solutions. An amphiphilic or lipophilic drug, such asmetronidazole, is partially or completely enclosed within this cagestructure, thereby increasing the solubility of the drug in aqueousmedia. Cyclodextrins have certain disadvantages, however, includingexpense, limitations of cyclodextrin solubility, incompatibility incertain vehicles, and potential for local and systemic toxicity.

Several authors have described the use of beta-cyclodextrin (BCD) incombination with metronidazole. Kata and Antal, Acta PharmaceuticaHungarica, 54:116-122 (1984), disclose a marked increase in the rate ofdissolution of metronidazole when dissolved in a solution containing BCDat 37° C. The stability of the BCD/metronidazole solutions is notaddressed. Major problems with the use of BCD to solubilize drugs suchas metronidazole is that BCD has a relatively low solubility in waterand is a relatively inefficient solubilizer, particularly for lipophilicor amphiphilic drugs such as metronidazole. Additionally, cyclodextrins,such as BCD and its derivatives, are expensive and the drug formulationscontaining BCD as a solubilizing agent likewise become expensive. A needexists for a way to increase the solubility of drugs which requires areduced concentration of BCD.

Solubility enhancing agents other than cyclodextrins have beendescribed. Yie W. Chien, Journal of Parenteral Science and Technology,38(1):32-36 (January 1984), discloses that niacinamide is a solubilityenhancing agent that can increase the water solubility of MTZ. Chienfurther discloses that the water soluble vitamins ascorbic acid, andpyridoxine are solubility enhancing agents for aqueous solutions. Chiendiscloses that the solubility of metronidazole in water increaseslinearly with relation to the concentration of these water solublevitamins in the solution. The Chien article is incorporated herein byreference. The prior art does not address the combination ofcyclodextrins, such as BCD, with other solubility enhancing agents, suchas niacinamide or other water soluble vitamins.

SUMMARY OF THE INVENTION

It has been surprisingly discovered that the combination of acyclodextrin and a second solubility enhancing agent, such asniacinamide or niacin, has a synergistic effect on the aqueoussolubility of amphiphilic or lipophilic chemical compounds such asmetronidazole. The second solubility enhancing agent may be other thanniacinamide or niacin. The synergistic effect provided by thecombination of cyclodextrin and the second solubility enhancing agentpermits the use of lower concentrations of cyclodextrins than would benecessary to obtain a desired level of solubility of the chemicalcompound in the absence of the second solubility enhancing agent.Because cyclodextrins are expensive, has limited aqueous solubility, andis not entirely free of toxicity, the invention provides an importantway to greatly reduce costs in the formulation and preparation ofpharmaceutical preparations, as well as to increase the solubilizingcapability of cyclodextrins such as BCD, and to obtain desiredconcentrations of pharmacologic compounds while minimizing the amount ofcyclodextrins used.

As used herein, the term “solubility enhancing agent” or “solubilityenhancer” means a chemical compound that, when present in solution in asolvent, increases the solubility of a second chemical compound, such asan active ingredient, in the solvent, but which chemical compound is notitself a solvent for the second chemical compound.

All concentrations referred to in this specification are % w/w, unlessindicated otherwise.

The invention is described below with reference to a particularcyclodextrin, BCD, and a particular chemical compound, metronidazole. Itis conceived, however, that the invention is applicable to othercyclodextrins, both crystalline and non-crystalline, including alpha andgamma cyclodextrins, and crystalline and non-crystalline derivativesthereof, and other amphiphilic and lipophilic chemical compounds besidesmetronidazole.

Physically stable aqueous solutions of higher than 0.75% metronidazole(MTZ) may be obtained by combining in the solution a first solubilityenhancing agent which is a cyclodextrin, such as beta-cyclodextrin(BCD), and a second solubility enhancing agent, such as niacinamide orniacin. The combination of the cyclodextrin and the second solubilityenhancing agent provides a synergistic effect in increasing thesolubility of MTZ in water. These discoveries permit the production ofaqueous MTZ solutions, including solutions that are gels, at levels of1% MTZ or higher. At such levels, MTZ may be effectively used as atopical medicament.

In one embodiment, the invention is an aqueous solution having aconcentration of MTZ higher than 0.75% w/w, preferably about 1% orhigher. The aqueous solution contains a cyclodextrin, such as BCD, as afirst solubility enhancing agent and a second solubility enhancingagent, such as niacin or niacinamide. Preferably, the level of each ofthe cyclodextrin and the second solubility enhancing agent is less thanthat which, in the absence of the other solubility enhancing agent,would provide for a dissolved concentration of the MTZ to the level ofthat present in the aqueous solution. If desired, however, the solutionmay contain an excess of the second solubility enhancing agent. Mostpreferably, the enhanced solubility of MTZ in the combination solutionis higher than the sum of the enhanced solubilities of MTZ in twosolutions, each of which contains a single solubility enhancer at theconcentration present in the combination solution. Preferably, thesolution is substantially free of aqueous solubility-enhancing agentsother than a cyclodextrin and the second solubility enhancing agent.Preferably, the solution is an aqueous gel.

In another embodiment, the invention is a method for the manufacture ofan aqueous solution of MTZ having a concentration greater than 0.75%,preferably about 1.0% or higher. The method includes combining MTZ andtwo solubility enhancing agents, one of which is a cyclodextrin such asBCD, in a water based solution wherein the concentration of the finalaqueous solution of MTZ is higher than 0.75%. Preferably, the level ofeach of the cyclodextrin and the second solubility enhancing agent isless than that which, in the absence of the other solubility enhancingagent, would provide for a dissolved concentration of the MTZ to thelevel of that present in the aqueous solution. If desired, however, anexcess of the second solubility enhancing agent may be used. Mostpreferably, the enhanced solubility of MTZ in the combination solutionis higher than the sum of the enhanced solubilities of MTZ in twosolutions, each of which contains a single solubility enhancer at theconcentration present in the combination solution. Preferably, a gellingagent is further combined in the solution, preferably after addition ofthe MTZ and the solubility-enhancing agents.

In another embodiment, the invention is a method for the treatment of adermatologic or mucosal disorder. The method includes topically applyingto affected areas an aqueous solution of MTZ and a cyclodextrin, such asBCD, and a second solubility enhancing agent, such as niacin orniacinamide., which solution has a concentration of MTZ higher than0.75%, preferably about 1.0% or higher. Preferably, the level of each ofthe cyclodextrin and the second solubility enhancing agent is less thanthat which, in the absence of the other solubility enhancing agent,would provide for a dissolved concentration of the MTZ to the level ofthat present in the aqueous solution. If desired, however, the solutionmay contain an excess of the second solubility enhancing agent. Mostpreferably, the enhanced solubility of MTZ in the combination solutionis higher than the sum of the enhanced solubilities of MTZ in twosolutions, each of which contains a single solubility enhancer at theconcentration present in the combination solution. Preferably, theaqueous solution is a gel.

In another embodiment, the invention is a kit for the treatment of adermatologic or mucosal disorder. The kit of the invention includes acontainer that contains an aqueous solution of MTZ and which aqueoussolution contains a first solubility enhancing agent which is acyclodextrin, such as BCD, and a second solubility enhancing agent suchas niacin or niacinamide. Preferably, the level of each of thecyclodextrin and the second solubility enhancing agent is less than thatwhich, in the absence of the other solubility enhancing agent, wouldprovide for a dissolved concentration of the MTZ to the level of thatpresent in the aqueous solution. If desired, however, the solution maycontain an excess of the second solubility enhancing agent. Mostpreferably, the enhanced solubility of MTZ in the combination solutionis higher than the sum of the enhanced solubilities of MTZ in twosolutions, each of which contains a single solubility enhancer at theconcentration present in the combination solution. Preferably, theaqueous solution is a gel.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a diagrammatic representation of a preferred embodiment ofthe kit of the invention.

DETAILED DESCRIPTION OF THE INVENTION

It has been unexpectedly discovered that stable aqueous solutions ofmetronidazole (MTZ) of greater than 0.75% w/w, and even about 1.0% orhigher, are able to be obtained by using a combination ofsolubility-enhancing agents, wherein one of the solubility enhancingagents is a cyclodextrin, such as BCD, and the second solubilityenhancing agent is other than a cyclodextrin. Examples of suitablesecond enhancing agents include niacin and niacinamide.

As used in this specification, the term “stable” refers to physical,rather than chemical, stability. In accordance with the invention, themetronidazole solutions of the invention are physically stable, that issubstantially no crystal or precipitate from solution, when stored atrefrigerated temperatures of 5° C. for at least 7 days.

The physically stable aqueous solutions of metronidazole atconcentrations greater than 0.75% are obtained without the substantialpresence of water-miscible organic solvents, such as ethyl alcohol orpropylene glycol, which may be irritating to intact or damaged skin ormucosal surfaces. The elimination of these organic solvents provides atherapeutic solution that has decreased potential for irritation andmakes the solutions especially good for treating topical dermatologicconditions, such as rosacea, that may be worsened by irritatingchemicals present in a therapeutic formulation. However, if desired,such organic solvents may be included in the solution, up to aconcentration of about 10%. In a most preferred embodiment, the aqueoussolutions are substantially free of organic solvents for MTZ.

The stable aqueous MTZ solutions of the invention have a concentrationof MTZ greater than 0.75% w/w. Preferably, the concentration of MTZ inthe solution of the invention is about 1.0%. In accordance with theinvention, the concentration of MTZ in aqueous solution may be evenhigher, such as 1.25%, 1.5%, 2.0%, or 2.5%, or more. At a level of 1% orhigher of MTZ, the aqueous solution may be effectively usedtherapeutically as a topical formulation.

The solution is preferably in the form of a gel. Therefore, the aqueousMTZ solution preferably contains a gelling agent. Any gelling agent thatis water-dispersible and forms an aqueous gel of substantially uniformconsistency is suitable for use in the solution of the invention so longas the gelling agent does not substantially interfere with the watersolubility of MTZ or with the therapeutic efficacy of the solution.“Substantially interfere” means that the inclusion of the gelling agentdecreases the solubility of MTZ to 0.75% w/w or less in aqueoussolution. A preferred gelling agent is hydroxyethylcellulose (NATROSOL™,Hercules Inc., Wilmington, Del., USA). Examples of other suitablegelling agents include carboxyvinyl polymers, such as CARBOPOL® 934,940, and 941 (Noveon, Inc., Akron, Ohio, USA).

The level of the cyclodextrin in the solution may be varied dependingupon the desired dissolved concentration of MTZ. In general, it ispreferable to use as low a concentration of cyclodextrin as possible toobtain the desired concentration of MTZ because cyclodextrins areexpensive, of limited aqueous solubility, not entirely free of toxicity,and the presence of cyclodextrin may be irritating to certain intact anddiseased skin and mucosal surfaces. In accordance with the invention,the concentration of cyclodextrin in aqueous solution may be between0.1% and 20%, or higher. Preferably, the concentration of cyclodextrinin the solution is no more than about 5% w/w. In the case ofbeta-cyclodextrin, the concentration in aqueous solution is limited byits solubility in water. An aqueous solution, such as a gel, ofbeta-cyclodextrin is saturated at a concentration of about 0.5% at 5° C.(refrigerator temperature).

The solutions, especially in gel formulation, are non-tacky,fast-drying, and cosmetically elegant. The solutions, including the gelformulations, are physically stable at 5° C. (refrigerator temperature)or room temperature conditions for at least 7 days. No crystal formationor precipitation is observed after one week at 5° C.

It is preferred that the aqueous solution of the invention besubstantially free of pharmacologically active compounds other than MTZhaving a water-solubility which is increased by the presence ofcyclodextrins. These other compounds may act as competitors for thesequestration sites within the cyclodextrin cage structure and reducethe MTZ solubility enhancement by the cyclodextrin. Multiple solutesthat are increased in solubility by cyclodextrins may be utilized in thesolutions so long as the level of cyclodextrin and the second solubilityenhancer in the solution is sufficiently high to result in the desireddissolved concentration of MTZ, even in the presence of the competitorsolute.

In a preferred embodiment of the invention, the amount of cyclodextrinin the solution is at a level below that which enhances thesolubilization of MTZ to the level desired, and a second solubilityenhancer, such as niacinamide or niacin, is included in the solution ata level that permits the desired concentration of MTZ in aqueoussolution to be attained. For example, if a stable 1% MTZ aqueoussolution is desired, 0.1% to 1.0% BCD may be used and an amount ofniacinamide or niacin may be combined in the solution to bring thesolubility of MTZ to 1%. The amount of niacinamide to be combined in thesolution is less than that which, without the presence of BCD in thesolution, can enhance the solubility of MTZ sufficiently to obtain a 1%solution of MTZ, or whatever level of MTZ is desired. In accordance withthis embodiment of the invention for a 1% aqueous solution of MTZ, theconcentration of BCD % w/w in the solution is preferably at a level of1.0% or less and the concentration of niacinamide or niacin equal to ormore than that of BCD.

The aqueous solutions, including the aqueous gels, of the invention maybe made in any way that results in a stable MTZ concentration of greaterthan 0.75%, preferably of 1.0% or higher. Preferably, the solubilityenhancers and the MTZ are combined in water, or a water-based solution,before the addition of a gelling agent, or at least before gelling ofthe solution occurs. Preferably, the solubility enhancers are dissolvedin water before addition of the MTZ.

In a preferred method of manufacture of the aqueous solution of theinvention, an aqueous solution of BCD and niacinamide or niacin isprepared, wherein the levels of BCD and niacinamide or niacin are asdescribed above. Metronidazole is then added to the solution. The amountof metronidazole added to the solution may be an amount calculated toprovide the desired concentration of MTZ or it may be an excess amountof MTZ. The solution is preferably stirred or agitated at an elevatedtemperature and then permitted to cool to room or refrigeratortemperature. A gelling agent, if desired, is preferably added at anytime after the addition of MTZ to the solution. Most preferably, thegelling agent is added to the solution after the agitation of thesolution, during the cooling of the solution, or following cooling ofthe solution.

The solutions of the invention, including gels, may be used for thetopical treatment of dermatologic or mucosal disorders that areresponsive to therapy with metronidazole. In accordance with the methodof treatment of the invention, a stable aqueous solution containingmetronidazole at a concentration higher than 0.75% w/w, preferably about1% or higher, is topically applied to skin or mucosal surfaces in needof such therapy. The applied solution preferably contains a cyclodextrinlike BCD, as described above, in combination with niacin or niacinamide,as described above.

The therapeutic method of the invention may be used to treat anydisorder that is responsive, or potentially responsive, to metronidazoletherapy. Examples of disorders that are suitably treated in accordancewith the invention include inflammatory lesions on the skin, oralmucosa, or vaginal mucosa, diabetic foot ulcers, and certain infectiousdiseases that may be treated topically. In a preferred embodiment, themethod of the invention is used to treat rosacea.

At concentrations of about 1% or higher, the application of themetronidazole solution is preferably only once daily. The solution isapplied on a daily basis, one or more times per day, for a timesufficient to produce an amelioration or a cure of the disorder. Incertain chronic disorders, the solution may be applied one or more timesdaily for a prolonged period to prevent worsening of the disorder.

In another embodiment of the invention, a kit (FIG. 1) is provided forthe topical treatment of skin or mucosal disorders. The kit containsajar 101 or other container suitable for holding an aqueousmetronidazole solution as described herein, and instructions (notillustrated) for applying the solution topically to affected areas ofthe skin or mucosal surface. Preferably, the metronidazole solution hasa concentration of metronidazole of about 1% or higher and theinstructions call for applying the metronidazole solution to affectedareas once daily. The jar 101 is preferably packaged within a box 102,upon which additional information, such as instructions, may be written.

The following non-limiting examples provide a further description of theinvention.

EXAMPLE 1

All solutions in the following examples contain the components listed asthe generic formula or gel vehicle shown in Table 1.

TABLE 1 COMPONENT % w/w Methylparaben 0.15 Propylparaben 0.05Phenoxethanol 0.7 Edetate sodium 0.05 Hydroxyethyl cellulose (HEC) 1.25Beta-cyclodextrin (BCD) As shown in Tables 2 to 6 Niacinamide or NiacinAs shown in Tables 2 to 6 Purified Water QS 100.00

Different solutions according to Table 1 were made with varyingconcentrations of beta-cyclodextrin (BCD). The solutions of BCD weremaintained at 5° C. monitored weekly for two weeks for signs of crystalor precipitate formation. The results are shown in Table 2. The datashow that the saturated BCD solubility in the aqueous solutions at 5° C.is about 0.5%.

TABLE 2 BCD % w/w Results after storage at 5° C. 0.5 Clear after 2 weeks0.6 Crystals formed after 2 weeks 0.7 Crystals at one week 0.9 Crystalsat one week 1.0 Crystals at one week 1.2 Crystals at one week 1.4Crystals at one week 1.5 Crystals at one week

EXAMPLE 2

Different concentrations of metronidazole were prepared with the gelvehicle of Example 1 containing 0.5% BCD. The metronidazole (MTZ)/BCDsolutions were maintained at 5° C. for one week. The results are shownin Table 3.

TABLE 3 BCD % w/w MTZ % w/w Result at 5° C., 1 week 0.5 0.9 Crystalsformed 0.5 0.8 Clear 0.5 0.7 Clear

From this study, the stable solubility of metronidazole in the gelvehicle containing 0.5% BCD at 5° C. was determined to be about 0.8%w/w.

EXAMPLE 3

A similar study using various concentrations of niacinamide showed thatthe concentration of niacinamide required to obtain a stable aqueous gelsolution of 1.0% metronidazole is about 3%. Various gel solutions ofTable 1 were prepared with a concentration of 1.0% metronidazole andcontaining either 0.5% or 1.0% BCD and differing concentrations ofniacinamide. The gels were maintained at 5° C. for one week to observefor precipitate or crystal formation. The results are shown in Table 4.

TABLE 4 BCD Niacinamide Metronidazole Results at 5° C., % w/w % w/w %w/w 1 week 0.5 0.5 1.0 Crystals formed 0.5 1.0 1.0 Clear 0.5 2.0 1.0Clear 1.0 0.5 1.0 Precipitate formed 1.0 1.0 1.0 Clear 1.0 2.0 1.0 Clear

The results in Table 4 show that concentrations of BCD and niacinamideas low as 0.5% and 1.0%, respectively, may be used together to obtain aphysically stable aqueous gel solution of 1.0% metronidazole.

EXAMPLE 4

Various gel solutions of Table 1 were prepared with a concentration of1.0% metronidazole and various concentrations of niacin. The pH wasadjusted to 5.0+/−0.15 with trolamine. The solutions were maintained at5° C. for one week to observe evidence of precipitation or crystalformation. The results are shown in Table 5.

TABLE 5 Niacin % w/w MTZ % w/w Results, 5° C., 1 week 2.0 1.0 Clear 1.81.0 Clear 1.5 1.0 Clear 1.2 1.0 Clear 1.0 1.0 Clear 0.75 1.0 Clear 0.51.0 Clear/Crystals formed* 0.25 1.0 Crystals formed 0.25 1.0 Crystalsformed 0.15 1.0 Crystals formed 0.10 1.0 Crystals formed *seven out ofeight samples showed crystal formation

The results in Table 5 show that the minimum concentration of niacinrequired to obtain a stable 1.0% metronidazole gel solution is greaterthan 0.5% and preferably about 0.75%.

EXAMPLE 5

Various solutions according to Table 1 with 1% metronidazole, 0.5%niacin, pH adjusted to 5.0+/−0.15 and varying concentrations of BCD. Thesolutions were maintained at 5° C. for one week to observe for crystalor precipitate formation. The results are shown in Table 6.

TABLE 6 BCD % w/w Niacin % w/w MTZ % w/w Results, 5° C., 1 week 0.2 0.51.0 Crystals formed 0.3 0.5 1.0 Crystals formed 0.5 0.5 1.0 Clear

As shown in Table 6, using a combination of 0.5% niacin and 0.5% BCD, astable 1.0% aqueous gel solution of metronidazole was produced.

The above data in Examples 1 to 5 show that BCD at its maximum solubleaqueous concentration raises the stable solubility of MTZ in aqueoussolution, such as a gel, at 5° C. by 0.1%, that is from 0.7% to 0.8%. A3% concentration of niacinamide is needed to increase MTZ aqueoussolubility by 0.3% to 1%. Thus, niacinamide at about 3% raises thephysically stable solubility of MTZ in aqueous gel by an amount that isabout 3 times the increase provided by the maximum soluble concentrationof BCD.

When BCD and niacinamide are both utilized in the solution, the twocompounds act synergistically to increase the solubility of MTZ inwater. The data in Examples 1 to 5 show that when BCD is added to anaqueous solution at an amount expected to yield an increase of 0.1% andniacinamide is added at a level that is one third the amount ofniacinamide that is able to raise the solubility of MTZ by 0.3%, thiscombination results in a solubility of MTZ that is 0.3% above itsunaided solubility.

Similar results were obtained using a 0.5% concentration of niacin, aconcentration which is below that which produces a stable 1% solution ofmetronidazole. When this concentration of niacin was combined with 0.5%BCD, a concentration that provides only a 0.1% increase in MTZ aqueoussolubility to 0.8%, the solubility of MTZ was synergistically increasedto 1% at a pH of about 5.

Various modifications of the above described invention will be evidentto those skilled in the art. For example, more than one cyclodextrin maybe used, such as beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.Similarly, the second solubility enhancing agent may be a multiplicityof solubility enhancing agents, such as both niacin and niacinamide. Itis intended that such modifications are included within the scope of thefollowing claims.

1. A method for making an aqueous composition containing a dissolvedconcentration of metronidazole greater than 0.75% w/w comprisingcombining metronidazole, beta-cyclodextrin (BCD), and niacin orniacinamide in an aqueous fluid, wherein the BCD and the niacin orniacinamide are combined in the aqueous fluid in amounts that provide asynergistic effect on the solubility of metronidazole.
 2. The method ofclaim 1 wherein the aqueous composition is physically stable when storedfor one week at 5° C.
 3. The method of claim 1 wherein the metronidazoleis added to the aqueous fluid after the BCD and the niacin orniacinamide are dissolved in the aqueous fluid.
 4. The method of claim 1which further comprises, after the combination of metronidazole, BCD,and the niacin or niacinamide, adding a gelling agent.
 5. The method ofclaim 1 wherein niacinamide but not niacin is combined.
 6. The method ofclaim 1 wherein niacin but not niacinamide is combined.
 7. An aqueouscomposition that is made by the method of claim
 1. 8. An aqueouscomposition that is made by the method of claim
 4. 9. An aqueouscomposition that is made by the method of claim
 5. 10. An aqueouscomposition that is made by the method of claim
 6. 11. A method for thetreatment of a dermatologic or mucosal disorder comprising topicallyapplying an effective amount of an aqueous composition of metronidazolehaving a concentration higher than 0.75% w/w to the site of the disorderand permitting the metronidazole to treat the disorder, wherein thecomposition comprises beta-cyclodextrin (BCD) and niacin or niacinamidein amounts that provide a synergistic effect on the solubility ofmetronidazole, and wherein the composition is physically stable whenstored for one week at 5° C.
 12. The method of claim 11 wherein theconcentration of metronidazole is 1% or higher.
 13. The method of claim12 wherein the application is once daily.
 14. The method of claim 11wherein the disorder is rosacea.
 15. The method of claim 11 wherein thecomposition comprises niacin and is substantially free of niacinamide.16. The method of claim 11 wherein the composition comprises niacinamideand is substantially free of niacin.
 17. The method of claim 11 whereinthe aqueous composition is a gel.
 18. A kit for the topical treatment ofdermatologic or mucosal disorders comprising a container and an aqueouscomposition of metronidazole, beta-cyclodextrin, and niacin orniacinamide within said container, wherein the concentration ofmetronidazole in said composition is higher than 0.75% w/w, wherein theamounts of betacyclodextrin and niacin or niacinamide are sufficient toprovide a synergistic effect on the solubility of metronidazole, andwherein the aqueous composition is physically stable when stored for oneweek at 5° C.
 19. The kit of claim 18 wherein the concentration ofniacin or niacinamide is 1.0% w/w or higher.
 20. The kit of claim 19wherein the concentration of beta-cyclodextrin is 0.5% w/w or higher.21. The kit of claim 18 wherein the concentration of metronidazole is 1%w/w or higher.
 22. The kit of claim 18 wherein the aqueous compositionis a gel.
 23. The kit of claim 18 wherein the composition containsniacinamide and is substantially free of niacin.
 24. The kit of claim 18wherein the composition contains niacin and is substantially free ofniacinamide.
 25. An aqueous solution that is physically stable for atleast one week at 5° C. comprising metronidazole, a first solubilityenhancing agent which is betacyclodextrin, and a second solubilityenhancing agent which is niacin or niacinamide, wherein in the solution,the concentration of metronidazole is 0.75% w/w or higher and the firstand second solubility enhancing agents are present in amounts thatprovide a synergistic effect on the solubility of metronidazole.
 26. Theaqueous solution of claim 25 wherein the concentration ofbetacyclodextrin is 0.5% w/w or higher.
 27. The aqueous solution ofclaim 25 wherein the concentration of niacinamide or niacin is 0.5% w/wor higher.
 28. The aqueous solution of claim 25 wherein the solubilityenhancing agent is niacinamide.
 29. The aqueous solution of claim 25wherein the solubility enhancing agent is niacin.
 30. The aqueoussolution of claim 25 which comprises niacinamide and does not compriseniacin.
 31. The aqueous solution of claim 25 wherein the concentrationof niacinamide or niacin is 1.0% w/w or higher.
 32. The aqueous solutionof claim 31 which comprises niacinamide and does not comprise niacin.33. The aqueous solution of claim 25 which is a gel.
 34. The solution ofclaim 25 wherein the concentration of metronidazole is 1.0% w/w orhigher.
 35. A method for increasing the solubility of metronidazole inaqueous fluid to a concentration of 0.75% w/w or higher comprisingcombining metronidazole, betacyclodextrin, and niacinamide or niacin inan aqueous fluid, wherein the betacyclodextrin and the niacinamide orniacin are present in amounts that provide a synergistic effect on thesolubility of metronidazole.
 36. The method of claim 35 wherein theconcentration of betacyclodextrin in the fluid is 0.5% w/w or more. 37.The method of claim 35 wherein the concentration of niacinamide orniacin in the fluid is 1.0% or higher.
 38. The method of claim 35wherein the aqueous fluid is a gel.
 39. The method of claim 35 whichcomprises combining niacinamide in the fluid.
 40. The method of claim 35which comprises combining niacin in the fluid.
 41. The method of claim35 wherein the solubility of metronidazole is increased to 1.0% w/w ormore.
 42. The method of claim 35 wherein the betacyclodextrin and theniacin or niacinamide are dissolved in the aqueous fluid before themetronidazole is combined in the fluid.
 43. The method of claim 35wherein a gelling agent is added to the fluid after the metronidazole,betacyclodextrin, and the niacin or niacinamide are combined in thefluid.
 44. A method for increasing the enhancing effect ofbetacyclodextrin on the solubility of metronidazole at a concentrationof 0.75% w/w or higher in aqueous fluid comprising combining niacin orniacinamide with the betacyclodextrin in the aqueous fluid in amountsthat provide a synergistic effect on the solubility of metronidazole.45. The method of claim 44 wherein the concentration of betacyclodextrinin the fluid is 0.5% or more.
 46. The method of claim 44 wherein theconcentration of niacin or niacinamide is 1.0% w/w or more.
 47. Themethod of claim 44 wherein the niacin or niacinamide is combined in thefluid with the betacyclodextrin and then metronidazole is added to thefluid.
 48. The method of claim 44 wherein niacin is combined with thebetacyclodextrin in the aqueous fluid.
 49. The method of claim 44wherein niacinamide is combined with the betacyclodextrin in the aqueousfluid.
 50. An aqueous solution comprising metronidazole at aconcentration of 0.75% w/w or higher, betacyclodextrin, and niacinamideor niacin, wherein the solution contains betacyclodextrin andniacinamide or niacin in amounts that provide a synergistic effect onthe solubility of metronidazole and wherein the solution is free ofcrystal or precipitate formation when stored for one week at 5° C. 51.The aqueous solution of claim 50 wherein the concentration ofmetronidazole is 1% w/w or higher.
 52. The aqueous solution of claim 50which is an aqueous gel solution.